Compounds having a 3-arylbutanal core are particularly useful as intermediates in the production of medetomidine, which is a 4-substituted imidazole that is employed as the active ingredient in antifouling products such as Selektope™ and, in the form of the S enantiomer (known as dexmedetomidine), as a therapeutic agent.
However, the synthesis of the 3-arylbutanal core required for the production of medetomidine is hampered by the need for the incorporation of a sterically-hindered 2,3-dimethyl phenyl group.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.
Processes for the synthesis of medetomidine using 3-arylbutanals (specifically, 3-(2,3-dimethylphenyl) butanal) as synthetic intermediates are described in, for example, WO 2013/014428, which describes the synthesis of 3-arylbutanals via palladium catalysed coupling of a corresponding aryl boronate and croton aldehyde.
WO 2012/120070 describes the synthesis of 3-arylbutenals via palladium catalysed Heck coupling between a corresponding aryl halide and crotyl alcohol.
WO 2012/069422 describes the synthesis of 3-arylbutenals via reaction of an aryl lithium reagent with 4,4-dimethoxy-2-butanone.
Previous routes to 3-arylbutanals have also been based on processes involving the reaction of styrene derivatives with carbon monoxide and hydrogen, in the presence of a rhodium catalyst (see, for example, U.S. Pat. No. 4,113,781); and Lewis acid-catalysed reactions of benzyl acetals with vinyl ethers (see, for example, WO 98/045237).
Such processes have numerous technical and economic disadvantages, particularly when utilised in industrial manufacture, such as: the need for extreme reaction conditions (such as very low or very high temperatures and/or increased pressure); the generation of toxic waste products; the need for excessive dilution of reagents; the need for purification through removal of unwanted by-products; and the need to use toxic and/or expensive reagents.